Recent studies from a number of laboratories implicate enzymatically- derived reactive nitrogen species (RNS) as a major neurotoxic stress in the Alzheimer's disease (AD) brain, as well as in other diverse medical conditions including septic shock, cardiovascular disease and amyotrophic lateral sclerosis (ALS). We have specifically measured protein and lipid nitration and our findings lead us to hypothesize that nitrative damage is a key factor in Alzheimer's disease. The findings that lead to this hypothesis are as follows. (1) Protein nitration products, specifically 3-nitro-tyrosine (3N02-Tyr) are increased 2-7 fold in regions of the AD brain where classical AD histopathology is found, but not in the cerebellum, which is relatively spaed in AD. (2) Lipid nitration products, specifically 5-nitro-gamma-tocopherol (5-NO2-gamma-toc), are correspondingly increased in affected regions of the AD brain. Lipid nitration is particularly severe, with 10-40% of the total gamma- tocopherol (gamma-toc) pool being nitrated in AD. (3) When fractionation studies are performed on AD brain tissue, mitochondrial lipids are found to be more heavily nitrated than bulk lipids. (4) We have discovered that the p38 mitogen-activated protein kinase, which controls the expression of the inducible nitric oxide synthase (iNOS) enzyme, is hyperactivated in affected regions of the AD brain. Activated p38 is found in association with the classical histopathological features of the disease (plaques and tangles) where extensive protein nitration has been shown to localize. These findings further suggest that gamma-tocopherol (gamma-toc), a naturally-occurring homolog of alpha-tocopherol (alpha- toc, vitamin E) may serve a heretofore unrecognized, protective function as a scavenger of RNS in the human brain. This possibility is highly germane to the clinical treatment of AD because alpha-tocopherol is now widely used in attempts to slow the progression of AD, while gamma- tocopherol supplementation has not been investigated. These observations clarify the relationship between oxidative stress and neuroinflammation, and offer immediate suggestions as to potentially new therapies for AD.